The human Y and inactive X chromosomes similarly modulate autosomal gene expression

Adrianna K San Roman; Helen Skaletsky; Alexander K Godfrey; Neha V Bokil; Levi Teitz; Isani Singh; Laura V Blanton; Daniel W Bellott; Tatyana Pyntikova; Julian Lange; Natalia Koutseva; Jennifer F Hughes; Laura Brown; Sidaly Phou; Ashley Buscetta; Paul Kruszka; Nicole Banks; Amalia Dutra; Evgenia Pak; Patricia C Lasutschinkow; Colleen Keen; Shanlee M Davis; Angela E Lin; Nicole R Tartaglia; Carole Samango-Sprouse; Maximilian Muenke; David C Page

doi:10.1101/2023.06.05.543763

The human Y and inactive X chromosomes similarly modulate autosomal gene expression

bioRxiv [Preprint]. 2023 Jun 7:2023.06.05.543763. doi: 10.1101/2023.06.05.543763.

Authors

Adrianna K San Roman¹, Helen Skaletsky^{1

2}, Alexander K Godfrey^{1

3}, Neha V Bokil^{1

3}, Levi Teitz^{1

3}, Isani Singh^{1

4}, Laura V Blanton¹, Daniel W Bellott¹, Tatyana Pyntikova¹, Julian Lange^{1

3}, Natalia Koutseva¹, Jennifer F Hughes¹, Laura Brown^{1

2}, Sidaly Phou^{1

2}, Ashley Buscetta⁵, Paul Kruszka⁵, Nicole Banks^{5

6}, Amalia Dutra⁷, Evgenia Pak⁷, Patricia C Lasutschinkow⁸, Colleen Keen⁸, Shanlee M Davis⁹, Angela E Lin¹⁰, Nicole R Tartaglia^{9

11}, Carole Samango-Sprouse^{8

12}, Maximilian Muenke⁵, David C Page^{1

3

2}

Affiliations

¹ Whitehead Institute; Cambridge, MA 02142, USA.
² Howard Hughes Medical Institute, Whitehead Institute; Cambridge, MA 02142, USA.
³ Department of Biology, Massachusetts Institute of Technology; Cambridge, MA 02139, USA.
⁴ Harvard Medical School, Boston, MA 02115, USA.
⁵ Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda; MD 20892, USA.
⁶ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Bethesda, MD 20892 USA.
⁷ Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health; Bethesda, MD 20892 USA.
⁸ Focus Foundation, Davidsonville, MD 21035, USA.
⁹ Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
¹⁰ Medical Genetics, Massachusetts General for Children, Boston, MA 02114, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Developmental Pediatrics, eXtraOrdinarY Kids Program, Children's Hospital Colorado, Aurora, CO 80011, USA.
¹² Department of Pediatrics, George Washington University, Washington, DC 20052, USA; Department of Human and Molecular Genetics, Florida International University, Miami, FL 33199, USA.

Abstract

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46^th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex-chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors - ZFX and ZFY - encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.

Keywords: CRISPR; Klinefelter syndrome; Sex chromosomes; Turner syndrome; X chromosome inactivation; aneuploidy; gene expression; sex differences; transcription factors.

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